Emerging treatment of endometriosis

Middle East Fertility Society Journal (2015) xxx, xxx–xxx

Middle East Fertility Society

Middle East Fertility Society Journal www.mefsjournal.org www.sciencedirect.com

REVIEW

Emerging treatment of endometriosis Aboubakr Elnashar Benha University Hospital, Egypt Received 24 December 2014; accepted 24 December 2014

KEYWORDS Endometriosis; Treatment

Abstract Current treatment of endometriosis is mainly based on surgery and ovarian suppressive agents (oral contraceptives, progestins, GnRh agonist and androgenic agents). Hormonal treatments are often associated with unwanted effects, delayed conception and recurrence of disease and symptoms when stopped. For these reasons, new drugs that aim new targets are required to cause regression of the disease & symptoms without adverse hypo-estrogenic effects. This review aims to provide an update on the new drugs used for treatment of endometriosis. These include the levonorgestrel-releasing intrauterine device, GnRH antagonists, aromatase inhibitors, selective estrogen-receptor modulators, progesterone antagonist, selective progesterone receptor modulators, angiogenesis inhibitors, and immunomodulatory drugs. Ó 2015 The Author. Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Levonorgestrel-releasing intrauterine device (LNG-IUD). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GnRH antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aromatase inhibitors (AIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Aromatase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Aromatase inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Uses in postmenopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Uses in premenopause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Selective estrogen receptor modulators (SERMs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

00 00 00 00 00 00 00 00 00 00

Peer review under responsibility of Middle East Fertility Society.

Production and hosting by Elsevier http://dx.doi.org/10.1016/j.mefs.2014.12.002 1110-5690 Ó 2015 The Author. Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Elnashar A Emerging treatment of endometriosis, Middle East Fertil Soc J (2015), http://dx.doi.org/10.1016/j.mefs.2014.12.002

2 6. 7. 8. 9. 10.

A. Elnashar Progesterone antagonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Selective progesterone receptor modulators (SPRM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angiogenesis inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Immunomodulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. Matrix metalloproteinase (MMP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2. 5-Fluorouracil. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.3. Thiazolidinediones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.4. Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Endometriosis is a common estrogen-dependent disorder that can result in substantial morbidity, including pelvic pain, multiple operations, and infertility. Current treatment of endometriosis is mainly based on surgery and ovarian suppressive agents. Approximately only half of women with endometriosis get pain relief from existing medical or surgical treatments. Currently available medical therapies are designed to suppress estrogen synthesis, inducing atrophy of ectopic endometriotic implants or interrupting the cycle of stimulation and bleeding. Oral contraceptive, androgenic agents, progestins and gonadotropin-releasing hormone analogues have all been successfully used in the treatment of endometriosis. Unfortunately, these hormonal treatments are often associated with unwanted effects caused by a hypo-estrogenic state. Furthermore, recurrence of disease and symptoms is quite common with all available drugs. An ideal treatment for endometriosis would induce regression of the disease and its symptoms without any adverse effects associated with a hypo-estrogenic state. None of these drugs can eradicate the disease and, in some cases, the substantial side effects limit the long-term use of these therapies. Current medical therapies for endometriosis result in delayed conception and have not been shown to provide any fertile benefit subsequent to treatment. For these reasons, new drugs that aim new targets are under development (1). These include the levonorgestrel-releasing intrauterine device, GnRH antagonists, aromatase inhibitors, selective estrogen-receptor modulators, progesterone antagonist, selective progesterone receptor modulators, angiogenesis inhibitors, and immunomodulatory drugs. 2. Levonorgestrel-releasing intrauterine device (LNG-IUD) Although oral progestogens for treatment of endometriosis are effective and cheap, their efficacy is significantly influenced by poor compliance and systemic side effects (2). LNG is a potent steroid widely used in oral contraceptives and subdermally implanted contraceptive devices. It is a T-shaped intrauterine system, developed as a contraceptive device which releases LNG in the uterine cavity. The release rate of LNG from the intrauterine releasing system is 20 lg per 24 h during the first year, and it slowly decreases throughout the 5 years of use. The released progestogen induces endometrial atrophy although ovulation is usually not suppressed. This results in hypomenorrhea or amenorrhea and reduced dysmenorrheal (3).

00 00 00 00 00 00 00 00 00 00 00

An increasing number of publications indicate an emerging role for the LNG-IUD in the treatment of endometriosis. In patients with surgically proven peritoneal as well as rectovaginal endometriosis, the first pilot studies showed a great improvement in pain control as well as a reduction in ultrasonographic dimensions of the rectovaginal nodules (3,4). A significant reduction of pain as well as staging of the disease observed in 34 women with laparoscopically confirmed minimal to moderate endometriosis over a period of 6 months (5). The LNG-IUD is an effective hormonal option for treating symptomatic endometriosis (minimal to moderate). With a continuation rate of 68% after 6 months, it has the potential for providing long-term therapy in a substantial number of sufferers. The presence of adhesions was, as expected, not altered. Two randomized trials (6,7) were published on LNG-IUD use in endometriosis. The first (6) study compared expectant management with immediate treatment with the LNG-IUD after laparoscopic surgery for symptomatic endometriosis in 40 women. Twelve months after surgery dysmenorrhea scores were significantly lower in the LNG-IUD group compared with the expectant management group. The second trial (7) compared the efficacy of an LNG-IUD and a GnRH-agonist analog in the control of chronic pelvic pain in 83 women with stage I–IV endometriosis during a period of 6 months. Both, the LNG-IUS and the GnRH-analogue were effective in the treatment of chronic pelvic pain-associated endometriosis, although no differences were observed between the two treatments. Although the exact mechanism of action of the LNG-IUD is unclear, recent evidence (8) shows that the LNGIUD delivers significant amounts of LNG into the peritoneal fluid, clearing up the local effect on the endometriotic implants which may be mediated through estrogen and progesterone receptors, most probably inducing decidualization. As peritoneal fluid levels of LNG were closely related to the levels in serum, this suggests a dominant hematogenous mechanism by which LNG reaches the peritoneal cavity. A Cochrane systematic review evaluated postoperative use of an LNG-IUD in women with endometriosis (9). Limited evidence from one small study has shown that postoperative use of the LNG-IUD reduces the recurrence of painful periods in women who have had surgery for endometriosis. There is a need for further, well-designed RCTs of this approach. In conclusion, for women with endometriosis who need long-term treatment, the LNG-IUD may be a treatment of choice since it permits the same system to be used for at least 5 years with no modifications in estrogen levels and few hypoestrogenic side effects (7). In the long term it is a low-cost therapy with usually fewer side effects than other progestogenic

Please cite this article in press as: Elnashar A Emerging treatment of endometriosis, Middle East Fertil Soc J (2015), http://dx.doi.org/10.1016/j.mefs.2014.12.002

Emerging treatment of endometriosis agents. Among the additional advantages of the LNG-IUS is the fact it requires only one medical intervention for its introduction every 5 years. This device could therefore become the treatment of choice for CPP-associated endometriosis in women who do not wish to conceive. Further studies are required before this device can be recommended as a treatment for endometriosis-associated pelvic pain. 3. GnRH antagonists Gonadotropin releasing hormone agonist analogues have one serious problem; when first administered, they cause an increase in LH and FSH secretion and an increase in estradiol production. For women with pelvic pain, the increase in ovarian estrogen production is associated with increased pelvic pain and decreased quality of life (10). However, the agonist phase is typically limited to the first 5–10 days of treatment. Recently, GnRH antagonists that immediately block GnRH effects have been developed for clinical use in endometriosis, leiomyoma, breast cancer, premenstrual syndrome, polycystic ovary syndrome, and ovulation induction for in vitro fertilization (IVF) (11). The main mechanism of action of the GnRH antagonists is competitive receptor occupancy, which results in the blockade of GnRH receptor dimerization, a biochemical process that is required for receptor activation. The antagonistic properties of GnRH exert their effect by competing with endogenous GnRH for pituitary binding sites (12). The GnRH antagonists suppress LH secretion in a dose-dependent manner. At small doses, the suppression of LH is minimal. At large doses, nearcomplete suppression of LH can be achieved. In one preliminary study, a total of fifteen women received 3 mg of cetrorelix (Cetrotide) weekly for eight weeks (13). Circulating estradiol was suppressed to a mean of 50 pg/ml. All patients reported a symptom-free period during GnRH antagonist treatment. Regression occurred in more than half of the cases and the degree of endometriosis declined to a mild stage on second look laparoscopy. Another GnRH antagonist, abarelix, has been demonstrated to be effective in the treatment of pelvic pain caused by endometriosis (14). However, side effects may have slowed the progress of the development of this antagonist for treatment of endometriosis. In conclusion, GnRH antagonists seem to be useful in the treatment of endometriosis in most cases. Furthermore, fewer side effects, such as postmenopausal symptoms, occur with this agent and no estradiol add-back is needed. The GnRH antagonist analogues may be superior to GnRH agonists because they produce immediate suppression of LH and FSH secretion and avoid the agonist phase of GnRH agonist therapy. In the future, new nonpeptic GnRH antagonists are expected to be available for oral administration. Although they are still under investigation, these agents have the potential to improve patients’ comfort and compliance (15).

3 local estrogen biosynthesis by the aromatase enzyme in endometriotic lesions. Aromatase activity is expressed in several types of cells in the reproductive system including the ovarian granulosa cell, the placental syncytiotrophoblasts and the testicular Leydig cells (16). Aromatase is the key enzyme in estrogen biosynthesis. It catalyzes the conversion of C19 steroids to estrogens (estrone and estradiol). Therefore, there are no important downstream enzymes to be affected, with the result that aromatase is an excellent target for inhibition of estradiol synthesis. In addition, because estrogen is needed to stimulate ectopic endometriotic tissues in patients with endometriosis and because of the in situ presence of aromatase in these tissues, blockage of aromatase activity in these endometriotic sites with an AI is a rational approach to medical treatment of endometriosis (17). In women with endometriosis, it has been shown that there is an increased expression of cytochrome P450 aromatase in endometrial tissue, but not in women without endometriosis (18). Although the normal endometrium contains no detectable levels of aromatase activity, this enzyme is induced to very high levels in endometriotic tissue by the inflammatory mediator prostaglandin estradiol (E2) to increase local estrogen production in the disease implants. 4.2. Aromatase inhibitors The AIs are classified into type I and type II inhibitors. Both types of inhibitors compete for binding to the active site. Enzyme activity is then permanently blocked due to an unbreakable bond between the inhibitor and enzyme protein (19). Several potent and selective third-generation AIs are available; of these, anastrozole and letrozole have substantial advantages over earlier agents in terms of efficacy and tolerability. AIs are FDA approved to treat postmenopausal women with estrogen receptor positive breast cancer refractory to tamoxifen. Although these agents have been widely used to treat postmenopausal or anovulatory patients with breast cancer, clinical experience with AIs in women with endometriosis is still limited (20). AIs act by blocking aromatase, which converts androstenedione to estrone, an estrogen derivative (21). Its mechanism of action is by decreasing local production of estrone causing a low estrogen milieu. Decreasing aromatase in the brain specifically is thought to decrease LH and FSH, which, in turn, leads to a decrease in estrogen levels as well. Because the initial response to the effects of AIs is a decrease in estrogen levels, there is an increase in FSH and LH. This increase in FSH and LH directly stimulates the ovary. Stimulating the ovary leads to an increased number of mature follicles (22). Therefore, using an AI can treat pain associated with endometriosis, but can also treat the infertility aspect when used for ovulation induction and in IVF protocols. The two AIs mainly used for endometriosis pain and infertility are anastrozole and letrozole, both third generation drugs.

4. Aromatase inhibitors (AIs)

4.3. Uses in postmenopause

4.1. Aromatase activity

In the first published report of the use of an AI (anastrozole) for the treatment of endometriosis, a 57 year old woman with severe recurrent endometriosis experienced complete relief of pain after 2 months of treatment. (23). Recently Mousa et al.

Medical treatments usually are directed at inhibiting estrogen action or its production from the ovaries and do not address

Please cite this article in press as: Elnashar A Emerging treatment of endometriosis, Middle East Fertil Soc J (2015), http://dx.doi.org/10.1016/j.mefs.2014.12.002

4 (24) found that Letrozole was superior to exemestane in relieving the endometriosis-associated pain in this postmenopausal woman. This suggests that patients may respond variably to different AIs. A post-menopausal woman with a large recurrent abdominal wall endometrioma was managed successfully with the combination of an AI, a progestin, and serial cyst aspiration (25). 4.4. Uses in premenopause In premenopausal women, an AI alone may induce ovarian folliculogenesis, and thus AIs are combined with a progestin, a combination oral contraceptive, or a GnRH analogue in order to prevent reflex increments in luteinizing hormone and follicle stimulating hormone. A small pilot study of 10 reproductive aged women demonstrated that a combination of letrozole (2.5 mg/day), norethindrone acetate (2.5 mg/day), calcium and vitamin D for 6 months is effective in both reducing laparoscopically visible endometriotic lesions and decreasing pelvic pain scores (26). In another study, two premenopausal sisters (24 and 26 years old) were diagnosed with endometriosis by laparoscopy and failed to respond to conventional treatment including oral contraceptives and GnRH analogues. An AI (anastrozole 1 mg/day) was given with progestin (200 mg/day) for 6 months. The treatment resulted in a rapid progressive reduction in symptoms with the maintenance of remission of symptoms and absence of endometriotic lesions for more than two years after treatment in both cases. Pregnancy was achieved in both cases after two years. Side effects were minimal and well tolerated by both patients (27). Two premenopausal patients with bladder endometriosis were treated with letrozole (2.5 mg/day), norethisterone acetate (2.5 mg/day), elemental calcium and vitamin D3 for 6 months (28). The double-drug regimen quickly improved pain and urinary symptoms in both patients. One patient had no significant adverse effect and continued the therapy for 14 months. The other patient developed myalgia and severe arthralgia; pain and urinary symptoms recurred few months after the interruption of the 6-month treatment and the patient underwent laparoscopic partial cystectomy. AIs improve pain and urinary symptoms in patients with bladder endometriosis; however, severe side effects of treatment may occur. These agents should be administered only to patients who refuse surgery and fail to respond to other therapies. In a non-randomized initial study, Amsterdam et al. evaluated 18 reproductive aged women with refractory pain from endometriosis who failed two other therapies (29). They were administered anastrozole 1 mg for 6 months in addition to a continuous oral contraceptive pill to prevent pregnancy. This study found there was a decrease in pain scores associated with the combination of anastrozole and OCP. Very recently, Letrozole given with combined pills achieved complete regression of recurrent endometriotic cysts and pain relief in all cases (30). After a 6-month washout of endometriosis hormone therapies, women took letrozole (2.5 mg), one tablet of 0.15 mg of desogestrel, and 0.03 mg of ethinyl estradiol, calcium (1200 mg), and vitamin D3 (800 IU) daily for 6 months. Disappearance of ovarian endometrioma and reduction in pelvic pain in all cases at the end of 6 months were observed. The size of ovarian endometriomas was reduced

A. Elnashar after 3 months. Pain scores decreased only after 1 month of treatment and continued decreasing in each treatment month. Overall, no significant change in bone density was detected. A prospective, randomized trial showed that 6 months of treatment with anastrozole (1 mg/day) and goserelin compared with goserelin alone increased the pain-free interval and decreased symptom recurrence rates in patients after surgery for severe endometriosis (31). 4.5. Side effects Side effects of AIs are rare, but include headaches and diarrhea. Because AIs decrease estrogen in local tissues, it can increase the risk of osteoporosis (32). One study found no change in bone density at 6 months after use of an AI with an oral contraceptive in premenopausal women, and another found a decrease in bone density with the use of AI with a GnRH agonist after 6 months of use in premenopausal women (33). One case report demonstrated that exemestane was used to successfully treat pain in refractory endometriosis and might be a better choice than other AIs because it is potentially bone sparing (24). Larger, randomized, controlled studies will need to be done to evaluate the effect of AIs on bone density of reproductive aged women. It is likely that if a true decrease in bone density is found, there will be time limitations such as with depo-provera, as well as recommendations to supplement calcium in these patients. Letrozole is the most common AI used for ovulation induction. It is given cyclically for infertility compared with continuously if used for pain (22). Letrozole is not FDA approved for this indication and there is a black box warning regarding using this medication in pregnant women. One study found that in 911 births that were conceived by using either clomiphene citrate (CC) or letrozole for ovulation induction, the rate of both chromosomal anomalies as well as major congenital malformations was the same in the CC and letrozole group (34). In conclusion, all three combinations were shown to decrease pain in patients with refractory endometriosis. Regimens which include combinations of an AI with a progestin or oral contraceptive will probably become more popular than combinations of an AI with a GnRH analogue because the former are cheaper with fewer side effects, and may be administered long term or for repeated courses (21). Limited data are available on the long-term course of pain symptoms after completion of treatment with AIs; however, some recent studies suggest that symptoms may recur at short-term follow-up (35). No severe adverse effect has been reported during treatment with AIs both in pre- and postmenopausal women. On the basis of the available data, administration of AIs should now be offered only to the small number of women who have severe pain despite previous surgical and hormonal therapies. Further research in the form of larger sample size randomized controlled trials will be required before recommending the routine use of these agents. 5. Selective estrogen receptor modulators (SERMs) Non-steroidal anti-estrogens that bind to estrogen receptors (ERs) and can act as either estrogen agonists or antagonists, depending on the target tissue, are known as SERMs (36). They can be targets toward the a- or b-subunits of the estrogen

Please cite this article in press as: Elnashar A Emerging treatment of endometriosis, Middle East Fertil Soc J (2015), http://dx.doi.org/10.1016/j.mefs.2014.12.002

Emerging treatment of endometriosis receptor. Raloxifene is a second-generation SERM that has been shown to prevent osteoporotic fractures and holds promise for the prevention of breast cancer. In contrast to tamoxifen, a first-generation SERM, raloxifene has an antiestrogenic effect on endometrial tissue. SERMs are best known for their use in menopause and breast cancer. There is emerging data indicating that this class of medication, specifically agonists toward the b-subunit, may be able to be used to treat endometriosis. The b-unit is felt to act on different targets than classic a-SERMs, such as bone, mammary and endometrium (37). SERMs directed toward the b-subunit have been found to have anti-inflammatory action in several rat models toward other inflammatory mediated diseases, such as inflammatory bowel disease and rheumatoid arthritis (38). One study demonstrated that SERMS resolved endometriosis in 40–75% of mice treated with a SERM directed toward the b-subunit (37). Its effects in human clinical studies are not yet known. 6. Progesterone antagonist Mifepristone (RU-486) is best known for its use in medical abortions (39). Mifepristone is an oral active progesterone antagonist at the receptor level. It also has a high affinity for progesterone and glucocorticoid II receptors. With its antiprogesterone effect, mifepristone prevents progesterone from exerting its action. It also has a direct inhibitory effect on human endometrial cells and it can modulate the estrogen and progesterone receptor expression in both eutopic and ectopic endometrium. Both mifepristone and onapristone another drug with progesterone antagonist properties have been shown to have promising effects on endometriosis in the rodent model (40,41). Several non-randomized small trials have demonstrated a reduction of pain, as well as decrease in visible disease at time of laparoscopy (42,43). These trials have all used 6100 mg. Kettel et al. published a series of studies of administration of different doses of mifepristone in women with endometriosis. A minimum dose of 50 mg mifepristone for six months demonstrated a significant regression in visible endometriotic lesions and a decrease in clinical symptoms. On the other hand, treatment of endometriosis patients with mifepristone 5 mg per day in an uncontrolled pilot study resulted in pain improvement but no change in endometriosis lesions, suggesting this dosage is too low to achieve acceptable efficacy (42). Side effects are usually seen with doses of P200 mg. These side effects are due to the antagonistic affinity of the drug to glucocorticoid receptors causing a hypoadrenal state. Further large randomized clinical trials on the use of mifepristone in women with endometriosis should be performed in the future. 7. Selective progesterone receptor modulators (SPRM) SPRM are novel progesterone receptor ligands with a high degree of endometrial selectivity that exhibit agonist/antagonist effects based on the target tissue, dose and presence or absence of progesterone (44). They have the potential to induce reversible amenorrhea through selective inhibition of endometrial proliferation, a direct effect on endometrial blood

5 vessels and the potential to suppress endometrial prostaglandin production in a tissue-specific manner without the systemic effects of estrogen deprivation, providing a rationale for the treatment of endometriosis-related pain (45). Asoprisnil is the first SPRM to reach an advanced stage of clinical development for the treatment of endometriosis. Asoprisnil can suppress both the menstrual cycle and endometrial growth (46). To date, there is only one published randomized, placebo-controlled trial (47) of asoprisnil (5, 10 and 25 mg/day) for 12 weeks in 130 women with a laparoscopic diagnosis of endometriosis who exhibited moderate or severe pelvic pain at baseline. All doses of asoprisnil reduced nonmenstrual pelvic pain similarly as well as dysmenorrhea; however, the effect on bleeding pattern was dose-dependent. A separate study with an identical design using different asoprisnil doses showed that 5 mg is the minimum effective dose for pain relief in subjects with endometriosis (48). SPRM have many potential benefits over other therapies. First, they can disrupt cycling in patients without the low-estrogen milieu that causes many side effects in GnRH agonists. In relationship with antiprogesterones, they are more specific for the progesterone receptors thus not inhibiting the glucocorticoid receptors as well (49). No serious, drug-related adverse events were reported during the treatment or follow-up period. A favorable safety and tolerability profile of asoprisnil with no signs of estrogen deprivation was reported. 8. Angiogenesis inhibitors Retrograde menstruation with peritoneal attachment is believed to lead to the development of endometriotic lesions. However, this shed endometrial tissue requires the establishment of a new blood supply in order to survive in the peritoneal cavity (50). The endometrium has angiogenic potential, and endometriotic lesions grow in areas with a rich vascularization, suggesting that angiogenesis is a prerequisite for endometriosis development. Therefore, inhibition of proangiogenic factors (e.g. VEGF and MMPs) may offer new therapeutic opportunities (51). Anti-vascular endothelial growth factor agents and other angiostatic drugs (i.e., TNP470, endostatin, anginex, rapamycin) have been studied in laboratory and animal models for treatment of endometriosis. The effectiveness of angiostatic compounds in reducing the growth of endometriotic lesions has been shown in the mouse model (52). Only one human study (53) has been performed thus far suggesting that the angiostatic (and immunomodulatory) compound thalidomide may be effective in women with relapsing endometriosis. A novel, non-hormonal, approach to treat endometriosis may be found in the use of statins. Statin originally developed to treat heart disease and prolong life expectancy, and statins lower blood cholesterol levels by inhibiting HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, an enzyme that controls the rate of cholesterol production (51). There are potentially very exciting other benefits, such as reducing the risks of diabetes, dementia and even osteoporosis. A recent report (54) demonstrated that statins also inhibit the growth of human endometrial stromal cells in vitro, which opens a promising new field in endometriosis research. Rapamycin is a widely used drug with antifungal, immunosuppressant and antiangiogenic effects. A recent animal study

Please cite this article in press as: Elnashar A Emerging treatment of endometriosis, Middle East Fertil Soc J (2015), http://dx.doi.org/10.1016/j.mefs.2014.12.002

6 demonstrated that administration of rapamycin significantly reduced the size of the endometriotic lesions (55). This was associated by inhibition of VEGF-mediated angiogenesis as indicated by a suppression of endothelial cell sprouting in vitro and a reduction of microvessel density in endometriotic lesions in vivo. Rapamycin induces regression of endometriotic lesions by inhibiting neovascularization and cell proliferation. Dopamine and its agonists, such as cabergoline (Cb2), promote VEGF receptor-2 (VEGFR-2) endocytosis in endothelial cells, preventing VEGF-VEGFR-2 binding and reducing neoangiogenesis (50). Recent study evaluated the anti-angiogenic properties of Cb2 on growth of established endometriosis lesions. A significant decrease in the percentage of active endometriotic lesions and cellular proliferation index was found with Cb2 treatment. Neoangiogenesis was reduced by Cb2 treatment, as observed at gross morphological level and by significant changes in gene expression. Cb2 treatment in experimental endometriosis has an anti-angiogenic effect acting through VEGFR-2 activation. These findings support the testing of dopamine agonists as a novel therapeutic approach to peritoneal endometriosis in humans. Recently, the effect of dopamine agonist quinagolide on endometriotic lesions in patients with endometriosis-associated hyperprolactinemia was evaluated (56). Quinagolide induced a 69.5% reduction in the size of the lesions, with 35% vanishing completely. By interfering with angiogenesis, enhancing fibrinolysis, and reducing inflammation, quinagolide reduces or eliminates peritoneal endometriotic lesions in women with endometriosis. The potential, limitations and challenges of antiangiogenic therapy for the treatment of endometriosis have been explored (57). Antiangiogenic agents tested so far have proven effective for preventing neo-vascularization of endometriotic lesions and are likely to be efficient for early-stage disease. However, antiangiogenic treatments may alter reproductive function by impairing physiological angiogenesis, the greatest concern being the potential risk of teratogenicity. The initial promise of vascular therapy has not yet been fulfilled, mainly due to the limited selectivity of the vascular therapies available. The ongoing evolution in genomics and proteomics is revolutionizing the discovery of novel, disease specific endothelial markers, leading to improved ligand-based treatments. Combining angiostatic agents and VDAs with medical and surgical therapies in an adjuvant setting, e.g. with a view to preventing relapse or improving drug efficacy, may serve to accelerate the introduction of vascular drugs in the context of endometriosis treatment. This would probably be the quickest and most efficient way of enhancing current treatment modalities. In conclusion, the vasculature is a promising target because of its genetic stability, easy access via the circulation and amplifying action during treatment. The administration of antiangiogenic drugs has been proved to reduce the establishment, maintenance and progression of endometriotic lesions in different laboratory and animal models; however, further investigations are required before clinical trials can be planned in humans. The role of antiangiogenic compounds in the treatment of endometriosis remains to be defined. It appears unlikely that antiangiogenic drugs may cure the symptoms caused by large endometriotic nodules that are mainly composed by fibromuscular tissue (58); on the contrary, these agents may have a role in the postoperative treatment of endometriosis

A. Elnashar to increase the pain free interval and decrease the recurrence of the disease. 9. Immunomodulators The mounting evidence shows that altered immune function plays a crucial role in the genesis and development of endometriosis. It has become clear that pelvic inflammation, increased macrophage activation and invasion of the extracellular matrix are potential targets for endometriosis treatment and/or prevention (51). Immunomodulators are thought to work by decreasing the inflammatory response to disease. The molecules that allow for ectopic endometrial cells to implant on the peritoneum and begin growing are thought to be mediated through this process (1). Most of these compounds have not been thoroughly tested in humans, but initial studies in rodent models are promising. This broad group of medications includes loxoribine, IFN-a 2 b and TNF-a inhibitors. Loxoribine is thought to stimulate natural killer cells, which then do not allow endometrial cells to implant in ectopic tissues. One small study in rat models showed that there was a significant reduction in amount of disease (59). IFN-a 2 b is another immunomodulator that has been shown to decrease endometriosis in animal models and in tissue cultures (1). The route of administration of this medication is by intraperitoneal placement during laparoscopy or by subcutaneous injections. Due to this invasive administration, this drug would likely be approved only for refractory disease. One small, prospective randomized study found that intraperitoneal treatment with IFN-a 2 b during surgery with a GnRH agonist postoperatively increased recurrence risk after surgery (60). One of the most promising interventions seems to be the selective blocking of TNF-a production. Therapeutic manipulation of the immune system through TNF-a inhibitors may be beneficial in women with endometriosis (61) TNF-a inhibitors, such as etanercept, are a new form of therapy mostly used for rheumatoid and autoimmune diseases. They work by decreasing production or release of TNF-a from macrophages. TNF-a inhibitors may have role in preventing disease progression or causing regression of early stage disease. In the rodent (61) and baboon model (62), it has been shown that TNF-a binding protein is able to inhibit the development of endometriosis and endometriosis-related adhesions. In humans, however, the evidence is not so promising. There is one case report of patient with advanced endometriosis who was on a TNF-a inhibitor and who showed no improvement of infertility or endometriosis based on laparoscopy after several years of taking the medication (63). A randomized placebo-controlled trial was designed with 21 women with severe pain and a rectovaginal nodule (64). After 1 month of observation, three infusions of an anti-TNF-alpha monoclonal antibody (infliximab; 5 mg/kg) or placebo were given. Surgery was performed 3 months later and follow-up continued for 6 months. Pain severity decreased during the treatment by 30% in both the placebo and infliximab groups. However, no effect of infliximab was observed for any of the outcome measures. After surgery, pain scores decreased in both groups to less than 20% of the initial value. Infliximab appears not to affect pain associated with deep endometriosis.

Please cite this article in press as: Elnashar A Emerging treatment of endometriosis, Middle East Fertil Soc J (2015), http://dx.doi.org/10.1016/j.mefs.2014.12.002

Emerging treatment of endometriosis In conclusion, there is no enough evidence to support the use of anti-TNF-alpha drugs in the management of women with endometriosis for the relief of pelvic pain (65). No evidence of clinical benefits of infliximab was found for endometriotic lesions, dysmenorrhea, dyspareunia or pelvic tenderness. Several cytokines may also play a role in the treatment of endometriosis. A major function of interleukin-12 (IL-12) and IL-18 is the regulation of the adaptive immune response (66). IL-12 induces other cytokines, particularly interferon-c (IFN-c), which coordinate the ensuing immune response. Intraperitoneal injection of IL-12 in a murine model of endometriosis demonstrated a significant reduction of ectopic endometrial implantation (67). Pentoxifylline, a phosphodiesterase inhibitor, is the first immune-modulator agent investigated for the treatment of endometriosis (68). Pentoxifylline inhibits phagocytosis and generation of toxic oxygen species and proteolytic enzymes by macrophages and granulocytes in vitro and in vivo. Moreover, pentoxifylline inhibits both TNF-a production by macrophages, and the proinflammatory action of TNF-a and IL-1 on granulocytes in vitro. One randomized controlled trial evaluated the effect of pentoxifylline on future fertility in infertile women with asymptomatic minimal or mild endometriosis (69). Patients were allocated to receive either a 12 month course of oral pentoxifylline (800 mg/day) or an oral placebo. The 12 month actuarial overall pregnancy rates were 31 and 18.5% in the pentoxifylline and placebo groups respectively. However, this difference was not statistically significant. Therefore, there is no evidence from this study that immunomodulation with pentoxifylline aids fertility in those women with minimal or mild endometriosis. A Cochrane systematic review to determine the effectiveness and safety of pentoxifylline, in the management of endometriosis in subfertile women showed that pentoxifylline had no significant effect on reduction of pain (70). There was no evidence of an increase in clinical pregnancy events in the pentoxifylline group compared with placebo. In conclusion, there is no enough evidence to support the use of pentoxifylline in the management of premenopausal women with endometriosis in terms of subfertility and relief of pain outcomes. Further studies including more infertile patients with endometriosis are desirable. 10. Others 10.1. Matrix metalloproteinase (MMP)

7 nificant decreases in the implant areas compared with the controls. Low-dose Dox caused regression of endometriosis in experimental rat model. 10.2. 5-Fluorouracil Recent study investigated the effects of antiproliferative drugs (anastrozole, methotrexate, and 5-fluorouracil [5-FU]) on the proliferation of endometriotic cells in vitro and in vivo (74). Although anastrozole, methotrexate, and progesterone were ineffective, 5-FU significantly decreased the proliferation of endometriotic cells in vitro and controlled the growth of both cells from ovarian endometrioma and deep infiltrating endometriosis. Considering common features between endometriotic cells and tumor cells, the use of 5-FU could be an option in the management of severe endometriosis. 10.3. Thiazolidinediones Thiazolidinediones (TZDs) do not impede conception and have been shown to reduce endometriotic lesions in animal models. One human study evaluated the effectiveness of a TZD in treating endometriosis-related pain. Participants were given rosiglitazone, 4 mg daily, for 6 months (75). Two of the 3 patients exhibited improvement in severity of symptoms and pain levels with a concurrent decrease in pain medication, while one experienced no change. Rosiglitazone was well tolerated by all patients. Combined with data gathered from studies in rats and nonhuman primates, the results from this study offer positive justification for using TZDs as a well-tolerated treatment for endometriosis that can address pain without impeding ovulation and without the need for add-back therapy. 10.4. Metformin In a rat model, Oner et al. (76) found that metformin and letrozole caused a statistically significant regression of endometriotic implants. Metformin suppresses the inflammatory response, the activation of aromatase enzyme and the proliferation in endometriotic stromal cells after culture in a sterile medium (77). In human, metformin 500 mg three times daily for 6 months resulted in a significant reduction in the patient’s complaints (P < 0.01) and in the serum levels of IL-6, IL-8 & VEGF, suggesting that it may have a therapeutic potential as an anti-endometriotic drug (78). Conflict of interest

The MMPs are a family of endopeptidases that are capable of degrading components of the extracellular matrix. It is important to many physiological and pathological processes, including embryo implantation, cyclic endometrial breakdown and endometriosis, and is regulated by its natural occurring inhibitor, tissue inhibitors of matrix metalloproteinase (TIMPs) (71). Suppressing the action of secreted MMPs from human ectopic endometrium with TIMP-1 significantly inhibited the establishment of endometriosis lesions in a nude mice model (72). Doxycycline (Dox) has a number of non-antibiotic properties. One of them is the inhibition of matrix metalloproteinase (MMP) activity. Recent study assessed the effects of Dox in a rat endometriosis model (73). Treatment with Dox caused sig-

The author declares that there is no conflict of interest. References (1) Ferrero S, Abbamonte LH, Anserini P, Remorgida V, Ragni N. Future perspectives in the medical treatment of endometriosis. Obstet Gynecol Surv 2005;60:817–26. (2) Huang H. Medical treatment of endometriosis. Chang Gung Med J 2008;31:431–40. (3) Fedele L, Bianchi S, Zanconato G, Portuese A, Raffaelli R. Use of a levonorgestrel-releasing intrauterine device in the treatment of rectovaginal endometriosis. Fertil Steril 2001;75:485–8.

Please cite this article in press as: Elnashar A Emerging treatment of endometriosis, Middle East Fertil Soc J (2015), http://dx.doi.org/10.1016/j.mefs.2014.12.002

8 (4) Vercellini P, Aimi G, Panazza S, De Giorgi O, Pesole A, Crosignani PG. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril 1999;72:505–8. (5) Lockhat FB, Emembolu JO, Konje JC. The evaluation of the effectiveness of an intrauterine-administered progestogen (levonorgestrel) in the symptomatic treatment of endometriosis and in the staging of the disease. Hum Reprod 2004;19:179–84. (6) Crosignani PG. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril 2003;80:305–9. (7) Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa E, Silva JC, Podgaec S, Bahamondes L. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20:1993–8. (8) Lockhat FB, Emembolu JE, Konje JC. Serum and peritoneal fluid levels of levonorgestrel in women with endometriosis who were treated with an intrauterine contraceptive device containing levonorgestrel. Fertil Steril 2005;83:398–404. (9) Abou-Setta AM, Al-Inany HG, Farquhar C. Levonorgestrelreleasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD005072. doi: 10.1002/ 14651858.CD005072.pub2. (10) Miller JD. Quantification of endometriosis-associated pain and quality of life during the stimulatory phase of gonadotropin releasing hormone agonist therapy: a double-blind, randomized placebo controlled trial. Am J Obstet Gynecol 2000;182:1483–8. (11) Huirne JA, Lambalk CB. Gonadotropin-releasing-hormone-receptor antagonists. Lancet 2001;358:1793–803. (12) Griesinger G, Felberbaum R, Diedrich K. GnRH-antagonists in reproductive medicine. Arch Gynecol Obstet 2005;273:71–8. (13) Kupker W, Felberbaum RE, Krapp M, Schill T, Malik E, Diedrich K. Use of GnRH antagonists in the treatment of endometriosis. Reprod Biomed Online 2002;5:12–6. (14) Martha PM, Gray ME, Campion M, Kuca B, Garnick MS. Initial safety profile and hormonal dose-response characteristics of the pure GnRH antagonist, abarelix-depot in women with endometriosis [abstract]. Gynecol Endocrinol 1999;13(S):104. (15) Finas D, Hornung D, Diedrich K, Schultze-Mosgau A. Cetrorelix in the treatment of female infertility and endometriosis. Expert Opin Pharmacother 2006;7:2155–68. (16) Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinshelwood MM, Graham-Lorence S, Amarneh B, Ito Y, Fisher CR, Michael MD. Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 1994;15:342–55. (17) Zeitoun KM, Bulun SE. Aromatase: a key molecule in the pathophysiology of endometriosis and a therapeutic target. Fertil Steril 1999;72:961–9. (18) Rodgers Allison K, Falcone Tommaso. Treatment strategies for endometriosis. Expert Opin Pharmacother 2008;9:243–55. (19) Buzdar AU, Robertson JF, Eiermann W, Nabholtz JM. An overview of the pharmacology and pharmacokinetics of the newer generation aromatase inhibitors anastrozole, letrozole, and exemestane. Cancer 2002;95:2006–16. (20) Oktay K, Hourvitz A, Sahin G, Oktem O, Safro B, Cil A, Bang H. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metab 2006;91:3885–90. (21) Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis? Fertil Steril 2006;85:1307–18. (22) Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate. Fertil Steril 2001;75:305–92.

A. Elnashar (23) Takayama K, Zeitoun K, Gunby RT, Sasano H, Carr BR, Bulun SE. Treatment of severe postmenopausal endometriosis with an Aromatase inhibitor. Fertil Steril 1998;69:709–13. (24) Mousa NA, Bedaiwy MA, Casper RF. Aromatase inhibitors in the treatment of severe endometriosis. Obstet Gynecol 2007;109:1421–3. (25) Sasson IE, Taylor HS. Aromatase inhibitor for treatment of a recurrent abdominal wall endometrioma in a postmenopausal woman. Fertil Steril 2009;92:1170–4. (26) Ailawadi RK, Jobanputra S, Kataria M, Gurates B, Bulun SE. Treatment of endometriosis and chronic pelvic pain with letrozole and norethindrone acetate: a pilot study. Fertil Steril 2004;81:290–6. (27) Shippen ER, West Jr WJ. Successful treatment of severe endometriosis in two premenopausal women with an Aromatase inhibitor. Fertil Steril 2004;81:1395–8. (28) Ferrero S, Biscaldi E, Luigi Venturini P, Remorgida V. Aromatase inhibitors in the treatment of bladder endometriosis. Gynecol Endocrinol 2010 [Epub ahead of print]. (29) Amsterdam LL, Gentry W, Jobanputra S, et al. Anastrozole and oral contraceptives: a novel treatment for endometriosis. Fertil Steril 2005;84:300–4. (30) Seal SL, Kamilya G, Mukherji J, De A, Ghosh D, Majhi AK. Aromatase inhibitors in recurrent ovarian endometriomas: report of five cases with literature review. Fertil Steril 2011;95:291–8. (31) Soysal S, Soysal ME, Ozer S, Gul N, Gezgin T. The effects of post-surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Hum Reprod 2004;19:160–7. (32) Buzdar AU. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial: an update. Clin Breast Cancer 2004;5(Suppl. ), S6 -12. (33) Soysal S, Soysal M, Ozer S, et al. The effects of post-surgical administration of goserelin plus anastrozole compared to goserelin alone in patients with severe endometriosis: a prospective randomized trial. Hum Reprod 2004;19:160–7. (34) Tulandi T, Martin J, Al-Fadhli R, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril 2006;85:1761–5. (35) Ferrero S, Venturini PL, Ragni N, Camerini G, Remorgida V. Pharmacological treatment of endometriosis: experience with aromatase inhibitors. Drugs 2009;29(69):943–52. (36) Vogelvang TE, van der Mooren MJ, Mijatovic V, Kenemans P. Emerging selective estrogen receptor modulators: special focus on effects on coronary heart disease in postmenopausal women. Drugs 2006;66:191–221. (37) Harris HA, Bruner-Tran KL, Zhang X, et al. A selective estrogen receptor- b agonists causes lesion regression in an experimentally induced model of endometriosis. Hum Reprod 2005;20:936–41. (38) Harris HA, Albert LM, Leathurby Y, et al. Evaluation of an estrogen receptor – b agonist in animal models of human disease. Endocrinology 2003;144:4241–9. (39) Jiang J, Wu RF, Wang ZH, Sun HC, Xu Z, Xiu HM. Effect of mifepristone on estrogen and progesterone receptors in human endometrial and endometriotic cells in vitro. Fertil Steril 2002;77:995–1000. (40) Stoeckermann K, Hegele-Hartung C, Chalisz K. Effects of the progesterone antagonist Onapristone (ZK 98 299) and ZK (136 799) on surgically induced endometriosis in intact rats. Hum Reprod 1995;10:3264–71. (41) Tjaden B, Galetto D, Woodruff JD, et al. Time-related effects of RU486 treatment in experimentally induced endometriosis in the rat. Fertil Steril 1993;59:437–40. (42) Kettel LM, Murphy AA, Mortola JF, et al. Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486). Am J Obstet Gynecol 1998;178:1151–6.

Please cite this article in press as: Elnashar A Emerging treatment of endometriosis, Middle East Fertil Soc J (2015), http://dx.doi.org/10.1016/j.mefs.2014.12.002

Emerging treatment of endometriosis (43) Kettel LM, Murphy AA, Morales AJ, et al. Treatment of endometriosis with the antiprogesterone mifepristone (RU486). Fertil Steril 1996;65:23–8. (44) Olive DL. Role of progesterone antagonists and new selective progesterone receptor modulators in reproductive health. Obstet Gynecol Surv 2002;57:S55–63. (45) Chwalisz K, Garg R, Brenner RM, Schubert G, Elger W. Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis. Ann N Y Acad Sci 2002;955:373–88. (46) DeManno D, Elger W, Garg R, Lee R, Schneider B, HessStumpp H, Schubert G, Chwalisz K. Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy. Steroids 2003;68:1019–32. (47) Chwalisz K, Larsen L, McCrary K, Edmonds A. Effects of the novel selective progesterone receptor modulator (SPRM) asoprisnil on selected hormonal parameters in subjects with leiomyomata. Fertil Steril 2004;82(Suppl. 2):S306. (48) Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger W. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev 2005;26:423–38. (49) Demanno D, Elger W, Garg R, et al. Asoprisnil (J867): a selective progesterone receptor modulator for gynaecological therapy. Steroids 2003;68:1019–32. (50) Novella-Maestre E, Carda C, Noguera I, Ruiz-Saurı´ A, Garcı´ aVelasco JA, Simo´n C, Pellicer A. Dopamine agonist administration causes a reduction in endometrial implants through modulation of angiogenesis in experimentally induced endometriosis. Hum Reprod 2009;24:1025–35. (51) Peter G, Hompes A, Mijatovic V. Endometriosis: the way forward. Gynecol Endocrinol 2007;23:5–12. (52) Nap AW, Griffioen AW, Dunselman GA, Bouma-Ter Steege JC, Thijssen VL, Evers JL, Groothuis PG. Antiangiogenesis therapy for endometriosis. J Clin Endocrinol Metab 2004;89:1089–95. (53) Scarpellini F, Sbracia M, Lecchini S, Scarpellini L. Antiangiogenesis treatment with thalidomide in endometriosis: a pilot study. Fertil Steril 2002;78(Suppl. 1):S87. (54) Piotrowski PC, Kwintkiewicz J, Rzepczynska IJ, Seval Y, Cakmak H, Arici A, Duleba AJ. Statins inhibit growth of human endometrial stromal cells independently of cholesterol availability. Biol Reprod 2006;75:107–11. (55) Laschke MW, Elitzsch A, Scheuer C, Holstein JH, Vollmar B, Menger MD. Rapamycin induces regression of endometriotic lesions by inhibiting neovascularization and cell proliferation. Br J Pharmacol 2006;149:137–44. (56) Go´mez Raul, Abad Antonio, Delgado Francisco, Tamarit Silvia, Simo´n Carlos, Pellicer Antonio. Effects of hyperprolactinemia treatment with the dopamine agonist quinagolide on endometriotic lesions in patients with endometriosis-associated hyperprolactinemia. Fer ster 2011;95:882–8. (57) Langendonckt A, Donnez J, Defre S, Dunselman G, Groothuis P. Antiangiogenic and vascular-disrupting agents in endometriosis: pitfalls and promises Molecular. Hum Reprod 2008;14:259–68. (58) Itoga T, Matsumoto T, Takeuchi H, Yamasaki S, Sasahara N, Hoshi T, et al. Fibrosis and smooth muscle metaplasia in rectovaginal endometriosis. Pathol Int 2003;53:371–5. (59) Keenan JA, Williams-Boyce PK, Massey PJ, et al. Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole. Fertil Steril 1999;72:135–41. (60) Acien P, Quereda F, Campos A, et al. Use of intraperitoneal interferon alpha-2b therapy after conservative surgery for endometriosis and postoperative medical treatment with depot gonadotropin-releasing hormone analog: a randomized clinical trial. Fertil Steril 2002;78:705–11.

9 (61) D’Antonio M, Martelli F, Peano S, Papoian R, Borrelli F. Ability of recombinant human TNF binding protein-1 (rhTBP-1) to inhibit the development of experimentally induced endometriosis in rats. J Reprod Immunol 2000;48:81–98. (62) D’Hooghe TM, Cuneo S, Nugent NP, Chai DC, Deer F, Mwenda JM. Recombinant human TNF binding protein-1 (r-hTBP-1) inhibits the development of endometriosis in baboons: a prospective, randomised, placebo- and drugcontrolled study. Fertil Steril 2001;76(Suppl. 1):S1. (63) Shakiba K, Falcone T. Tumour necrosis factor-a blockers: potential limitations in the management of advanced endometriosis? A case report. Hum Reprod 2006;21:2417–20. (64) Koninckx PR, Craessaerts M, Timmerman D, Cornillie F, Kennedy S. Anti-TNF-alpha treatment for deep endometriosisassociated pain: a randomized placebo-controlled trial. Hum Reprod 2008;23:2017–23. (65) Lv D, Song H, Shi G. Anti-TNF-alpha treatment for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2010;17(3):CD008088 [March]. (66) Huang HY, Chan SH, Yu HT, Wang HS, Lai CH, Soong YK. Interleukin-18 system messenger ribonucleic acid and protein expression in human endometrium during menstrual cycle. Fertil Steril 2006;86:905–13. (67) Somigliana E, Vigano P, Rossi G, Carinelli S, Vignali M, PaninaBordignon P. Endometrial ability to implant in ectopic sites can be prevented by interleukin-12 in a murine model of endometriosis. Hum Reprod 1999;14:2944–50. (68) Bessler H, Gilgal R, Djaldetti M, Zahavi I. Effect of pentoxifylline on the phagocytic activity, cAMP levels, and superoxide anion production by monocytes and polymorphonuclear cells. J Leu Biol 1986;40:747–54. (69) Balasch J, Creus M, Fa´bregues F, Carmona F, Martı´ nez-Roma´n S, Manau D, Vanrell JA. Pentoxifylline versus placebo in the treatment of infertility associated with minimal or mild endometriosis: a pilot randomized clinical trial. Hum Reprod 1997;12:2046–50. (70) Lv D, Song H, Li Y, Clarke J, Shi G. Pentoxifylline versus medical therapies for subfertile women with endometriosis. Cochrane Database Syst Rev 2009;8(3):CD007677 [July]. (71) Huang HY. The cytokine network during embryo implantation. Chang Gung Med J 2006;29:25–36. (72) Bruner KL, Matrisian LM, Rodgers WH, Gorstein F, Osteen KG. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest 1997;99:2851–7. (73) Akkaya P, Onalan G, Haberal N, Bayraktar N, Mu¨layim B, Zeyneloglu HB. Doxycycline causes regression of endometriotic implants: a rat model. Hum Reprod 2009;24:1900–8. (74) Ngoˆ C, Nicco C, Leconte M, Che´reau C, Weill B, Batteux F, Chapron C. Antiproliferative effects of anastrozole, methotrexate, and 5-fluorouracil on endometriosis in vitro and in vivo. Fertil Steril 2010;94:1632–8. (75) Moravek MB, Ward EA, Lebovic DI. Thiazolidinediones as therapy for endometriosis: a case series. Gynecol Obstet Invest 2009;68:167–70. (76) Oner G, Ozcelik B, Tucaygun M, Serin I, Ozturk F, Basbug M. The effects of metformin and letrozole on endometriosis and comparison of the two treatment agents in a rat model. Hum Reprod 2010;25:932–7. (77) Takemura Y, Osuga Y, Yoshino O, Hasegawa A, Hirata T, Hirota Y, et al. Metformin suppresses interleukin (IL)-1binduced IL-8 production, aromatase activation, and proliferation of endometriotic stromal cells. J Clin Endocrinol Metab 2007;92:3213–8. (78) Foda A, Abdel Aal I. Metformin as a new therapy for endometriosis, its effects on both clinical picture and cytokines profile. MEFSJ 2012;17:262–7.

Please cite this article in press as: Elnashar A Emerging treatment of endometriosis, Middle East Fertil Soc J (2015), http://dx.doi.org/10.1016/j.mefs.2014.12.002